An array of design strategies have been targeted toward minimizing failure of implanted microelectrodes by minimizing the chronic glial scar around the microelectrode under chronic conditions. Current approaches toward inhibiting the initiation of glial scarring range from altering the geometry, roughness, size, shape, and materials of the device. Studies have shown materials which mimic the nanotopography of the natural environment in vivo will consequently result in an improved biocompatible response. Nanofabrication of electrode arrays is being pursued in the field of neuronal electrophysiology to increase sampling capabilities. Literature shows a gap in research of nanotopography influence in the reduction of astrogliosis. The aim of this study was to determine optimal feature sizes for neural electrode fabrication, which was defined as eliciting a nonreactive astrocytic response. Nanopatterned surfaces were fabricated with nanoimprint lithography on poly(methyl methacrylate) surfaces. The rate of protein adsorption, quantity of protein adsorption, cell alignment, morphology, adhesion, proliferation, viability, and gene expression was compared between nanopatterned surfaces of different dimensions and non-nanopatterned control surfaces. Results of this study revealed that 3600 nanopatterned surfaces elicited less of a response when compared with the other patterned and non-nanopatterned surfaces. The surface instigated cell alignment along the nanopattern, less protein adsorption, less cell adhesion, proliferation and viability, inhibition of glial fibrillary acidic protein, and mitogen-activated protein kinase kinase 1 compared with all other substrates tested. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.